The potential utility of Receptor and/or Tissue-specific Imaging (with PET or SPECT) in the early detection and monitoring of subclinical neurodegenerative disease is widely recognized. PET/(F-18)Fluoro-DOPA (for Parkinson's disease) and SPECT/(I-123) IQNB (for Alzheimer's disease) studies clearly demonstrate the potential impact of such detection methods on the future management of neurodegenerative disorders. However, in order for such techniques to gain widespread clinical use, new radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT), the less expensive and more accessible of the two modalities, must be developed. The overall objective of this project is to develop novel I-123- labelled radiopharmaceuticals which are specific for the basal ganglia. In conjunction with SPECT, these agents could be used to provide a map of dopaminergic innervation in the human brain a relevant parameter in Parkinson's disease. Studies (in primates) on the metabolism of the neurotoxin MPTP and the biodistribution of its major metabolite, MPP+, clearly demonstrate specificity for and prolonged retention in the basal ganglia, coupled with high target/background ratios. The foregoing has provided an excellent model for the design of basal ganglia- specific radiopharmaceuticals. Based on existing Structure-Activity data of MPTP analogs, a number of lipid soluble radio-iodinated MPTP analogs have been proposed for basal ganglia-specific imaging with SPECT. These compounds will be synthesized, radiolabelled and screened using the following sequence: whole brain uptake (in rodents), MAO-catalyzed oxidation (in vitro), affinity for the dopamine uptake system (in vitro), selective basal ganglia accumulation (in vitro) and neurotoxicity (in vitro and in vivo). Those compounds which exhibit a profile similar to MPTP without exhibiting neurotoxicity will be further evaluated in the Squirrel monkey (autoradiographically) as potential basal ganglia-specific imaging agents. The sequence of experiments is such that undesirable compounds will be discarded in the early stages of the screening process.